(1) Dietary pharmacological retinoic acid inhibited papilloma to carcinoma conversion in the two stage system of skin carcinogenesis, but was without effect in the complete carcinogenesis protocol, in female SENCAR mice. The inhibition of conversion in the two-stage system was also evident when mice were switched from the physiological (3microg/g) to the pharmacological dose (30microg/g) or vice versa at week 20, which corresponds to maximal papilloma incidence. In situ hybridization analysis revealed a strong down regulation of the retinoic acid receptor RARalpha and concomitant up regulation of the retinoid receptor RXRalpha in skin carcinoma. (2) Transformation of NIH-3T3 cells with the ras oncogene rendered the cells unable to metabolize retinoic acid at the same time as they became refractory to the drug, as measured by lack of transglutaminase induction, cell adhesion and the inhibition of AP-1 activity. Retinoid receptor transcripts were not altered in a major way in the ras cells, suggesting regulation at the protein level. (3) Retinoid deficiency caused morular squamous metaplasia of the simple columnar epithelium of the murine cervix uteri. This metaplastic tissue, at variance with the simple-columnar epithelium, expressed retinoic acid receptor RARgamma and estrogen receptor transcripts, thus providing an example of nutritional control of steroid receptor expression in a hormone-dependent epithelium. (4) In studies of nutritional vitamin A deficiency, the naturally thymectomized homozygous nude mouse was found to lose its liver retinyl palmitate reserves and to show consequent signs of epithelial squamous metaplasia much earlier than its heterozygous control. Thus, immunodeficiency should be considered a facilitating factor in the development of vitamin A deficiency.